Adenosine analogues

Fig. 4. Aliphatic adenosine analogues with bioad-spectmm antiviral activity.

Aminoimidazole-4-carboxamide ribonucleoside (also known as AICA riboside or AICAR). An adenosine analogue that is taken up into cells by adenosine transporters and converted by adenosine kinase to the monophosphorylated nucleotide form, ZMP. ZMP is an analogue of AMP that activates the AMP-activated protein kinase (AMPK), for which acadesine or AICAR can be used as a pharmacological activator. 

The first pharmacological agent shown to activate AMPK was 5-aminoimidazole-4-carboxamide (AICA) riboside, also known as acadesine. This adenosine analogue is taken up into cells by adenosine transporters and phosphoiylated by adenosine kinase to the mono-phosphorylated form, AICA ribotide or ZMP. ZMP accumulates inside cells to higher concentrations than the concentration of AICA riboside present in the medium, and it mimics both effects of AMP on AMPK system (allosteric activation and inhibition of... 

The reaction of adenosine 5 -phosphoric imidazolide with adenosine analogues on a polyuridylic acid template is discussed in reference [158]. Another polymerization of oligoadenylates (pA)4 and (pA)6 on a polyuridylic acid template in an aqueous system... 

Mamos P, Aerschot AAV, Weyns NJ, Hardewijn PA (1992) Straightforward c-8 alkylation of adenosine analogues with tetraalkyltin reagents. Tet Lett 33 2413—2416... 

Reaction of adenosine analogues with DMAD in acetic acid results in the formation of oxopyrimidopurine esters, 477 (Equation 205). The isomeric compounds, 479, can be prepared from the intramolecular cyclization of... 

Dolphin, A. C., Forda, S. R. and Scott, R. H. Calcium-dependent currents in cultured rat dorsal root ganglion neurons are inhibited by an adenosine analogue. /. Physiol. (Lond.) 373 47-61,1986. 

Azaguanine and thioguanine are catabolized by guanase, and both the purinethiones are degraded by xanthine oxidase. Methylation and demethylation is an important factor in the activity of the thiopurihes and certain adenine or adenosine analogues also. 

Didanosine (ddl, Videx) is an adenosine analogue with activity against HIV-1, HIV-2, and HTLV-I. It is approved as part of a multidrug regimen for the therapy of HIV infection and is also used as postexposure HIV prophylaxis. 

Adenosine analogues where the furanose ring was replaced with alternative dihydro- and tetrahydrofurans were prepared from 6-chloro-9-(4-methylenetetrahydrofuran-3-yl)-9/7-purine <2002T4865>. Of particular interest was the transformation of the exocyclic alkene on the THF ring first by dihydroxylation, then elimination to yield (4-(6-aminopurin-9-yl)-2,5-dihydrofuran-3-yl)methanol after amination of the purine ring at C-6. This A-alkenylpurine was reduced (Pd/C, H2, 25 psi, 73% yield) to provide the tetrahydrofuran-3-yl derivative. 

As part of an investigation of the binding of adenosine analogues to an active site of mammalian adenosine deaminase, the structure and conformations of 2,8-diazaadenosine 29, and other isoteric analogs of adenosine 30, have been modeled using ab initio calculations and molecular mechanics (MM-I-) <2003MI152>. 

There is evidence that in cerebral ischaemia adenosine may have protective effects, since it inhibits the release of many excitatory neurotransmitters, such as glutamate, and it also stabilises the membrane potential. Unfortunately, adenosine has an extremely short half-life, but recently nucleoside (adenosine) transport inhibitors, e.g. draflazine, have been developed that prevent the endothelial uptake and breakdown of adenosine and prolong its beneficial effects. Nucleoside transport inhibitors also have myocardial protective properties and may have a role in organ preservation prior to transplantation. Adenosine also has an antinociceptive function and various adenosine analogues have antinociceptive activity, which correlates with their affinity for the A1 receptors (Lipkowski and co-workers 1996). 

Karlsten, R., Gordh, T., Post, C. Local antinociceptive and hyperalgesic effects in in the formalin test after peripheral administration of adenosine analogues in mice, Pharmacol. Toxicol 1992, 70, 434-438. 

Aliphatic adenosine analogues with broad-spectrum antiviral ucLivily... 

Adenosine analogues modified at the 2 position were studied systematically at the hA3AR in binding and functional assays of adenosine 3, 5 -cyclic phosphate (cAMP) (Fig. 6.5). Certain 2-ether derivatives were particularly potent in binding... 

A series of 8-alkynyladenosines reported by Volpini et al. (2001) represents the first example of structural adenosine analogues, with the intact ribose moiety, which behave as selective antagonists at hA3 adenosine receptor. The antagonistic effect was provided by the introduction of different alkynyl chains at the C-8 position of the purine nucleus. Compound 26 (Fig. 7.14) showed high level of selectivity at hA3 versus all other receptor subtypes, albeit showing low affinity in comparison with other heterocyclic molecules previously described. 

Reeves JJ, Jones CA, Sheehan MJ, Vardey CJ, Whelan CJ (1997) Adenosine A3 receptors promote degranulation of rat mast cells both in vitro and in vivo. Inflamm Res 46(5) 180-184 Ribeiro JA, Walker J (1975) The effects of adenosine triphosphate and adenosine diphosphate on transmission at the rat and frog neuromuscular junctions. Br J Pharmacol 54(2) 213-218 Ribeiro JA, Sebastiao AM (1984) Enhancement of tetrodotoxin-induced axonal blockade by adenosine, adenosine analogues, dibutyryl cyclic AMP and methylxanthines in the frog sciatic nerve. Br J Pharmacol 83(2) 485—492... 

Siddiqui, S.M. etal. Search for New Purine- and Ribose-Modified Adenosine Analogues as Selective Agonists and Antagonists at Adenosine Receptors. 2.4 1995 [180]... 

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